Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials.

Abstract

BACKGROUND AND AIMS\nElevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE.\n\n\nMETHODS\nPost-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n\u202f=\u202f4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies.\n\n\nRESULTS\nMedian (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5\u202fmg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0\u202fmg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50\u202fmg/dL (p-interaction vs. Lp(a)\u202f<\u202f50\u202fmg/dL: 0.0549).\n\n\nCONCLUSIONS\nIn this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels.